Appendix B

Literature Review

The committee conducted a literature review to find and evaluate content related to the safety and effectiveness of 10 U.S. Food and Drug Administration (FDA) priority active pharmaceutical ingredients (APIs) used in topical formulations. These 10 APIs were selected because FDA expressed interest in these compounds (see Box B-1).

In coordination with one of the National Academies of Sciences, Engineering, and Medicine’s senior research librarians, the committee constructed a literature search strategy that would produce a body of research that could inform its work. An initial search queried six databases (Medline, Embase, PubMed, Scopus, ClinicalTrials.gov, and Toxnet). Results from search one were limited to peer-reviewed articles published in the English language without any date restrictions, including human, animal, and in vitro studies. Editorials, commentaries, letters, and notes were excluded. A complete description of the syntax used can be found at the end of this appendix. This search resulted in 1,476 articles with potential relevance to the committee’s charge.

In an effort to refine its search, the committee conducted a focused search to concentrate on the topical application of FDA-priority ingredients for the explicit treatment of pain. In this search, the committee also included ketamine as an API of interest. This focused search used the same six databases as the broad search, as well as the same inclusion and exclusion parameters, and produced 240 articles with potential relevance to the committee’s charge.

To produce a more comprehensive report on the safety and effectiveness of ingredients used in compounded topical pain creams across a

broader list of compounds, the committee expanded its search strategy to include nine additional APIs. A broad and focused search were performed for these additional nine ingredients, employing the same parameters as the searches for the FDA-prioritized ingredients, but differed only in the set of ingredients queried (see Box B-2). The broad and focused searches for the additional ingredients produced 7,103 and 203 articles, respectively.

All literature results were combined and an initial screen was performed to eliminate articles not relevant to the study’s scope. A total of 7,203 articles were removed for either discussing topical application to the eye, or not discussing the treatment of pain in the title, keywords, or abstract of the article. After this first screen, 1,792 articles remained and were scored based on their level of evidence as determined by the study

design. Based on the committee’s research questions, the scope of the literature was limited to the topical application of any of the 20 ingredients to intact skin. This second screen for content relevance was carried out by committee members, and resulted in a total of 169 articles. See Figure B-1

for a flowchart that depicts the inclusion of articles in the committee’s literature review.

Of these 169 articles that were relevant to the study’s charge, all randomized controlled trials (RCTs) (29 from the literature search, and 1 identified in a systematic review from the literature search) were evaluated for their risk of bias. Committee members used the 2019 revised Cochrane Risk-of-Bias Tool for randomized trials to evaluate each RCT for potential biases that could affect the reported outcomes.¹ Committee members assessed each RCT in five domains: (1) bias arising from the randomization process, (2) bias due to deviations from intended interventions, (3) bias due to missing outcome data, (4) bias in measurement of the outcome, and (5) bias in selection of the reported result. Committee members assigned an overall risk of bias to each RCT based on the responses in each domain. An overall assessment of “low risk of bias” meant that there was a low risk of bias in each of the domains. “Some concerns” was reached if at least one domain was judged to raise some concern of bias, but no domain was at high risk of bias. Finally, a determination of “high risk of bias” was assigned to RCTs for which multiple domains raised some concern of bias in a manner that substantially lowered confidence in the result, or if there was high risk of bias for at least one domain.

Search Strategies

FDA-Priority Ingredients Broad Search
Date performed: January 9, 2019
Articles obtained: 1,476

Databases: Embase, Medline, PubMed, Scopus, Toxnet, ClinicalTrials.gov

Search Parameters:

1900 to present

Peer-reviewed articles

English language

International

___________________

¹ For more information on the risk of bias assessment used, see Sterne, J. A. C., J. Savović, M. J. Page, R. G. Elbers, N. S. Blencowe, I. Boutron, C. J. Cates, H.-Y. Cheng, M. S. Corbett, S. M. Eldridge, J. R. Emberson, M. A. Hernán, S. Hopewell, A. Hróbjartsson, D. R. Junqueira, P. Jüni, J. J. Kirkham, T. Lasserson, T. Li, A. McAleenan, B. C. Reeves, S. Shepperd, I. Shrier, L. A. Stewart, K. Tilling, I. R. White, P. F. Whiting, and J. P. T. Higgins. 2019. RoB 2: A revised tool for assessing risk of bias in randomised trials. BMJ 366:I4898.

Search Terms:

1. Ingredients
   1. Amitriptyline
   2. Baclofen
   3. Clonidine
   4. Cyclobenzaprine
   5. Gabapentin
   6. Meloxicam
   7. Memantine
   8. Orphenadrine
   9. Topiramate
   10. Tramadol
2. Targeted Search Terms
   1. Drug dosage form
      1. Creams
      2. Rubs
      3. Topical
      4. Skin absorption
      5. Transdermal drug administration
3. Outcomes
   1. Bioavailability
   2. Drug-related side effects and adverse reactions
   3. Effectiveness
   4. Pharmacokinetics
   5. Safety

FDA-Priority Ingredients Focused Search
Date performed: April 22, 2019
Articles obtained: 240

Databases: Embase, Medline, PubMed, Scopus, Toxnet, ClinicalTrials.gov

Search Parameters:

1900 to present

Peer-reviewed articles

English language

International

Search Terms:

1. Ingredients
   1. Amitriptyline
   2. Baclofen
   3. Clonidine

1. 4. Cyclobenzaprine
   5. Gabapentin
   6. Ketamine
   7. Meloxicam
   8. Memantine
   9. Orphenadrine
   10. Topiramate
   11. Tramadol
2. Targeted Search Terms
   1. Drug dosage form
      1. Creams
      2. Rubs
      3. Topical
      4. Skin absorption
      5. Transdermal drug administration
3. Outcomes
   1. Drug-related side effects and adverse reactions
   2. Pharmacokinetics
   3. Pain management

Additional Ingredients Broad Search
Date performed: May 31, 2019
Articles obtained: 7,103

Databases: Embase, Medline, PubMed, Scopus, Toxnet, ClinicalTrials.gov

Search Parameters:

1900 to present

Peer-reviewed articles

English language

International

Search Terms:

1. Ingredients
   1. Bupivicaine
   2. Cannabidiol
   3. Carbamazepine
   4. Dexamethasone
   5. Doxepin
   6. Ketamine²
   7. Naproxen

___________________

² The search for articles on ketamine using this strategy was performed on May 3, 2019.

1. 8. Nifedipine
   9. Pentoxifylline
2. Targeted Search Terms
   1. Drug dosage form
      1. Creams
      2. Rubs
      3. Topical
      4. Skin absorption
      5. Transdermal drug administration
3. Outcomes
   1. Bioavailability
   2. Drug-related side effects and adverse reactions
   3. Effectiveness
   4. Pharmacokinetics
   5. Safety

Additional Ingredients Focused Search
Date performed: April 30, 2019
Articles obtained: 203

Databases: Embase, Medline, PubMed, Scopus, Toxnet, ClinicalTrials.gov

Search Parameters:

1900 to present

Peer-reviewed articles

English language

International

Search Terms:

1. Ingredients
   1. Bupivacaine
   2. Cannabidiol
   3. Carbamazepine
   4. Dexamethasone
   5. Doxepin
   6. Ketamine³
   7. Naproxen
   8. Nifedipine
   9. Pentoxifylline

___________________

³ The search for articles on ketamine using this strategy was performed on March 28, 2019.

2. Targeted Search Terms
   1. Drug dosage form
      1. Creams
      2. Rubs
      3. Topical
      4. Skin absorption
      5. Transdermal drug administration
3. Outcomes
   1. Drug-related side effects and adverse reactions
   2. Pharmacokinetics
   3. Pain management

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